Both methamphetamine dependence and HIV disease can result in central nervous system (CNS) damage. The overall aim of this Program Project is to determine the influence of current and past methamphetamine dependence on the emergence of HIV-associated neurocognitive disorders. Background: As the incidence of HIV infections/new cases of AIDS attributable to homosexual/bisexual risk has declined, the proportion of cases related to drug abuse has risen. Methamphetamine use may contribute to HIV neurotoxicity both by facilitating transport of HIV into the CNS and by activating the same excitotoxic pathways that have been implicated in neural damage from HIV. Program Aims: 1) to define the influence of methamphetamine on expression of HIV neurobehavioral disorders; 2) to delineate the neurobiological bases of these disorders. Methods: This Program has five interacting Scientific Projects linked by a Core. Projects on Neuropsychology, MR Morphometry, and MR Spectroscopy explore the anatomic and functional effects of HIV and methamphetamine. Projects on Neuropathology and CSF Virology/Markers explore the mechanisms and pathways of neural damage. The general plan calls for recruiting 180 HIV+ and 120 HIV- methamphetamine dependent (METH+) persons and 180 HIV+ and 120 HIV- controls with a negative history of methamphetamine abuse and/or dependence (METH-). Subjects will be examined in a longitudinal study with annual multidisciplinary evaluations (medical, neurobehavioral). Subsets of participants will receive MR morphometric, MR spectroscopic, and neuropathologic studies. Significance: Both methamphetamine and HIV infection can damage the brain; the joint effects of these factors require exploration. Our studies on anatomic and functional brain changes in vivo linked to neuropathologic studies can address molecular mechanisms and selective neuronal vulnerability. The CSF studies will determine if CSF is an appropriate window into CNS events. Linking this Program to the NIMH funded HIV Neurobehavioral Research Center (HNRC) allows us to take advantage of the critical mass of investigators and staff with expertise in longitudinal neurobehavioral research on HIV, and capitalizes on availability of resources for evaluating and tracking participants, and for data management and statistics, thereby maximizing the economy of this study of methamphetamine dependent individuals.